Abstract
The transcription factor hepatocyte nuclear factor 4 A (HNF4A) controls the metabolic features of several endodermal epithelia. Both HNF4A and HNF4G are redundant in the intestine and it remains unclear whether HNF4A alone controls intestinal lipid metabolism. Here we show that intestinal HNF4A is not required for intestinal lipid metabolism per se, but unexpectedly influences whole-body energy expenditure in diet-induced obesity (DIO). Deletion of intestinal HNF4A caused mice to become DIO-resistant with a preference for fat as an energy substrate and energetic changes in association with white adipose tissue (WAT) beiging. Intestinal HNF4A is crucial for the fat-induced release of glucose-dependent insulinotropic polypeptide (GIP), while the reintroduction of a stabilized GIP analog rescues the DIO resistance phenotype of the mutant mice. Our study provides evidence that intestinal HNF4A plays a non-redundant role in whole-body lipid homeostasis and points to a non-cell-autonomous regulatory circuit for body-fat management.
Highlights
Obesity represents a major worldwide epidemic problem, with more than 1.3 billion adults being considered overweight[1]
We observed a significant reduction in high-fat diet (HFD)-induced weight gain in HNF4AΔIEC mutants, starting at 8 weeks post HFD feeding both in males (Fig. 1a) and females (Supplementary Fig. 1)
Our findings point to a nonessential role of Hepatocyte nuclear factor 4A (HNF4A) in regulating fatty-acid transport and metabolism in the intestinal epithelium
Summary
Obesity represents a major worldwide epidemic problem, with more than 1.3 billion adults being considered overweight[1]. To investigate the intestinal role of HNF4A in this context, we used a murine conditional deletion (HNF4AΔIEC) previously shown to exhibit minor phenotypes without impacting nutrition, whole-body energy metabolism, and weight management under a normal diet[12,13]. This mouse model uses the VillinCre transgene to drive Cre expression exclusively in the intestinal epithelium since homozygosity for the unconditional null Hnf4a allele is embryonic lethal[14]. We found that it produced resistance to dietinduced obesity (DIO) via non-cell-autonomous mechanisms involving GIP
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